Tagrisso already had an AURA of success in EGFR-mutated NSCLC, but will FLAURA help move its use to First-Line?

by Arnold DuBell
| Sep 10, 2017

Co-authored by Linda Zhao, Ph.D.

The treatment of lung cancer is rapidly becoming more segmented as molecular markers are identified, defining subgroups of essentially different diseases. Although NSCLC has also been an epicenter for the recent wave of immunotherapy approvals, major advances have been made with a flow of new targeted therapies for patients with driver mutations. The list of actionable driver mutations has been growing, with recent U.S. FDA approvals for agents targeting such as ROS1 rearrangements (Xalkori®, crizotinib, Pfizer) or BRAF V600E mutations [Tafinlar® (dabrafenib, Novartis) plus Mekinist® (trametinib, Novartis)] added to approved agents targeting EGFR mutations and ALK rearrangements.

EGFR mutations occur in approximately 10% of Caucasian patients with NSCLC and could be as high as 50% in Asian patients (1). Agents that are approved to treat EGFR mutated tumors in patients with NSCLC include the tyrosine kinase inhibitors (TKI) Tarceva® (erlotinib, Astellas / Genentech / Roche / Chugai), Iressa® (gefitinib, AstraZeneca), Gilotrif® (afatinib, Boehringer Ingelheim), and Tagrisso® (osimertinib, AstraZeneca). Tagrisso was approved for patients with EGFR T790M mutation-positive NSCLC following progression on or after EGFR TKI therapy based on the results of three studies [the phase II AURA-extension (2) and AURA2 trials (3) and phase III AURA3 (4)]. Following the first accelerated approval in November 2015 in the United States, a wave of quick global approvals soon followed (Europe, February 2016; Japan, March 2016; China; March 2017), and Tagrisso has quickly become the agent of choice for the treatment of relapsed patients with T790M mutations (5).

However, AstraZeneca also desired to position Tagrisso as a front-line option. It did so with the Phase III FLAURA trial which directly compared Tagrisso (80 mg/day orally) to a standard of care (SoC) EGFR TKI (either Iressa 250 mg/day or Tarceva 150 mg/day, both orally) in 566 untreated locally advanced or metastatic EGFR mutation positive NSCLC patients, which was an early spotlight at the 2017 ESMO Conference (6). Cross-over to Tagrisso was allowed for patients in the SoC arm upon central confirmation of disease progression and T790M mutation positivity. The primary endpoint was met as Tagrisso significantly improved PFS by investigator assessment compared to the current SoC (18.9 months compared to 10.2 months, HR 0.46, p < 0.0001). Notably, the PFS Kaplan-Meier curves separated very early, and the PFS benefit was demonstrated across all subgroups. More encouragingly, the level of PFS improvement with Tagrisso over SoC were also observed in patients both with and without central nervous system (CNS) metastases (15.2 months versus 9.6 months in patients with CNS metastases, HR 0.47, p=0.0009, n=116; 19.1 months versus 10.9 months in patients without CNS metastases, HR 0.46, p<0.001, n=440). The differences in objective response rate were not significant (80% versus 76%, OR 1.28, p=0.2335); however, the median duration of response was doubled with Tagrisso (17.2 months versus 8.5 months). The median overall survival was not reached in either Tagrisso or SoC arm at this time; not surprising as these data are only 25% mature. At this early stage, Tagrisso just missed meeting the threshold for significance in overall survival (HR 0.63, p = 0.0068. Note that a p-value of <0.0015 was required for significance at this level of maturity).

The safety profiles between the Tagrisso and the SoC arms were very comparable, but Tagrisso was associated with lower rates of Grade ≥ 3 drug-related adverse events (AEs; 18% versus 28%) and lower discontinuation rates (13% versus 18%). Common toxicities of all grades that differed between the two arms included dermatitis acneiform (25% versus 48%), AST increase (9% versus 25%) and ALT increase (6% versus 27%).

While physicians, quite understandably, may wait for final OS data, the data presented at ESMO 2017 leave no doubt that Tagrisso is an effective agent for first-line therapy for advanced EGFR mutation positive NSCLC. Given the rather large number of possible options, the success of FLAURA is raising important questions. How will physicians choose it among the current first-line EGFR TKI options? Moreover, dacomitinib (Pfizer), also recently shown an improved PFS compared to Iressa (14.7 months versus 9.2 months, HR 0.59, p <.0001) as a first-line option for these patients in the ARCHER 1050 trial (7), thereby adding a fourth possible competitor to the mix. Will doctors use Tagrisso in first line and push use of the other TKIs to later lines of treatment, or will physicians reserve Tagrisso for patients who become resistant to these other TKIs? An argument that could potentially sway physicians to use Tagrisso only in relapsed patients it that there is currently no data showing that the earlier approved TKIs will work for patients after they failed first line Tagrisso.

However, other arguments could sway the day for first-line Tagrisso. Hata et al (8) presented data suggesting that T790M EGFR mutations arise both from pre-existing clones as well as evolution of initially EGFRT790M-negative drug-tolerant cells. Although further data will need to be provided, perhaps Tagrisso’s activity against pre-existing T790M clones can prevent or delay resistance to EGFR TKIs, thus providing a clinically meaningful prolongation of PFS for patients with the optimal utilization of all available options. Another argument in Tagrisso’s favor could be its activity in patients with CNS metastases although Dr. Tony Mok, the discussant for this presentation, noted that CNS metastases were not a stratification factor. Ultimately, overall survival data could help physicians choose the optimal sequence of agents. If this data proves to be longer than approximately 27 months (an approximation by Dr. Mok reflecting the survival of patients treated with a currently approved TKI in the first-line followed by Tagrisso), then FLAURA will extend Tagrisso’s “AURA” into the first-line setting.